ReviewAntimicrobial use and bacterial resistance
Introduction
Antibiotics are unique therapeutic agents in several respects. The use of antimicrobials is directed towards invading organisms rather than creating alterations in host physiology. Antibiotic use in an individual patient may result in changes in microbial ecology that has the potential to affect others: the benefit to the individual must be measured against the risk to public health. We are facing an epidemic of bacterial resistance that is at least partially due to overuse and misuse of antibiotics. The tendency in the past has been to rely on the development of new drugs to overcome resistance. However, bacteria that are resistant to virtually all antibiotics are being seen and a more prudent approach would be control of excessive antibiotic use.
Shortly after the introduction of penicillin in the 1940s, resistance developed in Staphylococcus aureus followed by resistance to methicillin and, more recently, glycopeptides. As antibiotics have been developed and used, resistance has emerged in many other species. Although not proven, considerable evidence suggests that antibiotic use is causally linked to the selection of resistance in bacteria. However, the exact quantitative relationship between antibiotic use and resistance is unknown, as is the relative importance of infection control and antibiotic control efforts to reduce rates of resistance. Half of all antibiotic use in the environment is estimated to come from animal and food sources; the contribution of this use to resistance in humans is still being debated, and is not considered in this paper.
Bacterial resistance was initially thought to be a problem primarily in acute care hospitals but the overuse of antibiotics in the outpatient setting has also been associated with the development of resistance in several organisms. As a result, treatment of conditions commonly seen in the outpatient arena such as acute otitis media, acute cystitis, conjunctivitis [1] and acne [2] has become increasingly difficult. Spread of resistance between acute care hospitals, extended care facilities and outpatient clinics has also contributed to an epidemic of resistance that has been termed ‘antibiotic armageddon’ [3].
Antibiotics are the second most commonly prescribed class of drugs in the United States. It is estimated that 1/3 of patients receive antibiotics during hospitalization and that 50% of this use is unnecessary [4]. The financial costs of these drugs are astronomical: antibiotics account for 30–50% of the average hospital's drug budget, with total annual expenditure approaching seven billion dollars. Among the other potential consequences of increased antibiotic use is the selection of resistance in bacteria. Although not proven definitively, considerable evidence suggests a causal relationship between antibiotic use and the selection of resistance [5], [6], [7], [8], [9]10
[11]. Conversely, control of antibiotic use has resulted in improvements in susceptibility [8], [9]12[13]. In this review recent evidence linking antibiotic use and resistance, as well as approaches to control antimicrobial usage, are explored. We also discuss approaches used to control antimicrobial usage and their impact on resistance.
Section snippets
Antimicrobial use and development of resistance
Drug resistance in bacteria was likely to have been present to some degree prior to the modern antibiotic era [14]. However, the maintenance and spread of resistance determinants has increased in parallel with excessive use of antimicrobials in both inpatient and outpatient settings. Studies performed in hospitals have suggested a relationship between use and resistance with third generation cephalosporins and both Gram-negative rods [15] and methicillin-resistant Staphylococcus aureus (MRSA)
Does decreased antibiotic use result in decreased resistance?
The data on whether decreases in the use of antibiotics result in improved antibiotic susceptibilities are strongly suggestive but not conclusive. Early mathematical models suggested that once a resistant gene becomes widely disseminated, reductions in use of the antibiotic to which the organism is resistant will have little effect on its prevalence. More recent models suggest that reductions in hospital antibiotic use will result in a relatively rapid decline (over months) in prevalence of a
Strategies to control antibiotic use
A number of strategies have been proposed to modify antibiotic use in an attempt to improve outcomes (including a reduction in rates of resistance) and decrease costs. In spite of a general consensus that antibiotic use is excessive and needs to be moderated, a recent survey of hospitals participating in the Intensive Care Antimicrobial Resistance Project showed that only 38% had some form of strategy to control antibiotic use in place [39]. The most effective means of decreasing spread of
Educational programs
Several different educational approaches have been tried, with the rationale that deficient knowledge plays at least a part in inappropriate antibiotic use. Educational programs have included lectures, newsletters, clinical pharmacy or antibiotic team consultations, and development of clinical guidelines. The outcomes of such programs are difficult to assess owing to the complex variables involved in the educational process [28]. The most effective form of education is individual instruction by
Antibiotic formulary restriction
Formulary restriction is an effective means of limiting antibiotic choices. Studies have demonstrated that restricted formularies result in cost savings without adversely affecting outcomes [43]. The effect of formulary management on bacterial resistance has not been formally evaluated. A theoretical concern is that focused use of a relatively small number of antimicrobial agents will ultimately encourage development of resistance.
Prior approval programs
A variety of use-justification approaches have been designed to improve antibiotic utilization. These include telephone approval by an infectious disease specialist, automatic stop orders, and antibiotic order forms that require justification for the prescribed drug after it is dispensed from the pharmacy. Prior approval programs have been effective in decreasing antibiotic costs without compromising outcomes and clinical benefits have been seen as well. At Indiana University Medical Center a
Computer assisted management programs
Medical decision making involving the use of antibiotics is complex and requires integration of large amounts of data. Computers have the potential for making the necessary information available and assisting in the appropriate choice of antibiotics. Evans et al. [45] implemented a comprehensive antiinfectives monitoring program at the Latter-day Saints Hospital in Utah, USA, which included a computerized decision-support program linked to computer- based patient records. After initiation of
Antibiotic cycling
Cycling (or rotation), the scheduled alternation of use of varying classes of antibiotics, is emerging as an important strategy to decrease resistance. Early experience with cycling of aminoglycosides in the 1980s suggested that resistance to gentamicin and tobramycin could be decreased by use of amikacin [46]. Preliminary studies suggest that cycling of antibiotics in special care units may modify resistance patterns. In a study of ventilator-associated pneumonia after cardiac surgery a single
Conclusions
Antibiotics can decrease patient morbidity due to infections and can be life saving drugs as well. However, their high efficacy and relative lack of adverse effects has resulted in overuse in many situations, and increasing resistance to available drugs has become a worldwide problem. Although it is difficult to prove that a reduction in antibiotic use will reduce rates of resistance, recent evidence strongly suggests that this is a critical component of the solution. International efforts to
Update
In June 2000, the Centers for Disease Control and Prevention released its Draft Public Health Action Plan to Combat Antibacterial Resistance [50]. This plan promotes concrete steps with measurable outcomes that will reduce antimicrobial resistance in the United States. Part Two of the plan will be developed at a later date and will address international issues. The published plan contains four elements: Surveillance, Prevention and Control, Research, and Product Development. A common theme
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
- of special interest
- of outstanding interest
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